Molecular mechanism underlying sialic acid as an essential nutrient for brain development and cognition

Abstract

The early stages of neurodevelopment in infants are crucial for establishing neural structures and synaptic connections that influence brain biochemistry well into adulthood. This postnatal period of rapid neural growth is of critical importance for cell migration, neurite outgrowth, synaptic plasticity, and axon fasciculation. These processes thus place an unusually high demand on the intracellular pool of nutrients and biochemical precursors. Sialic acid (Sia), a family of 9-carbon sugar acids, occurs in large amounts in human milk oligosaccharides and is an essential component of brain gangliosides and sialylated glycoproteins, particularly as precursors for the synthesis of the polysialic acid (polySia) glycan that post-translationally modify the cell membrane-associated neural cell adhesion molecules (NCAM). Human milk is noteworthy in containing exceptionally high levels of Sia-glycoconjugates. The predominate form of Sia in human milk is N-acetylneuraminic acid (Neu5Ac). Infant formula, however, contains low levels of Sia consisting of both Neu5Ac and N-glycolyneuraminic acid (Neu5Gc). Current studies implicate Neu5Gc in several human inflammatory diseases. Polysialylated NCAM and neural gangliosides both play critical roles in mediating cell-to-cell interactions important for neuronal outgrowth, synaptic connectivity, and memory formation. A diet rich in Sia also increases the level of Sia in the brains of postnatal piglets, the expression level of 2 learning-related genes, and enhances learning and memory.

Conflict of interest statement

Author disclosure: B. Wang, no conflicts of interest. Bing Wang is presently employed by Nestle Research Center, Beijing, China.

Figures

Figure 1

Members of the Sia family. (A) Neu5Ac (present in neuroinvasive bacteria, human tissues, and foods). (B) Neu5Gc (present in trout eggs, some foods, and human tumors). (C) KDN (present in fish eggs and ovarian fluid, human fetal RBC, and human cancers. Reproduced with permission from (27). KDN, ketodeoxynonulosonic acid; Neu5Ac, N-acetylneuraminic acid; Neu5Gc, N-glycolylneuraminic acid; Sia, sialic acid.

Figure 2

Metabolic fate of how exogenous Sia and learning influences cellular function during neurodevelopment. Role and mechanism of neuronal gangliosides and polySia-NCAM in memory formation. (1) Exogenous (dietary) Sia in the food from milk oligosaccharides, glycoprotein, and gangliosides are digested and absorbed in the gastrointestinal system by bacterial and other neuraminidases (18, 27). (2) Much of the Sia is excreted in the stool and urine. (3) Sia is synthesized in the cell in the cytoplasm and transported into the nucleus where it is activated with CTP to form the activated nucleotide donor of Sia, CMP-Sia. CMP-Sia returns to the cytoplasm where it is then transported into the Golgi compartment and serves as the donor substrate of Sia for the sialyltransferases, including ST8Sia IV and ST8Sia II. CMP-Sia exerts negative feedback inhibition on GNE, the key bifunctional cytoplasmic enzyme that regulates the biosynthesis of Sia, thus limiting excess production of free Sia (69). GNE activity is low in neonates (49). (4) Exogenous sialylglycoconjugates can also be recycled from the extracellular fluid into lysosomes by receptor-mediated endocytosis. Lysosomal sialidases can cleave the Sia, which is then transported into the cytoplasm to be reutilized for the synthesis of CMP-Sia and, ultimately, new sialylglycoconjugates. (5) In the Golgi apparatus, the mono- and ST8Sia catalyze the transfer of Sia residues from the activated sugar nucleotide, CMP-Sia, to endogenous acceptors, including gangliosides and the NCAM. The intracellular concentration of Sia regulates the synthesis of polySia on NCAM (69). (6) Normal brain development and active learning increase the requirement for sialylated structures, including brain gangliosides and polySia-NCAM (, ,). (7) Upregulation of the level of ST8Sia IV mRNA significantly correlates with the level of GNE mRNA in the liver, hippocampus, and frontal cortex (66). This suggests that both GNE and ST8Sia IV may function in tandem to increase the synthesis of polySia on NCAM during times of high Sia demand, e.g., learning and brain growth. Under these conditions, the inhibitory feedback of CMP-Sia on GNE is minimized. (8) The mechanism whereby ST8Sia IV or other signaling molecules may upregulate GNE expression is not fully understood. It is also unclear if gangliosides may upregulate GNE expression during development. (9) The detailed molecular mechanisms underlying how neuronal gangliosides and polySia-NCAM may modulate memory formation, as shown, is under study. Figure modified from Wang et al. (27, 66). GNE, UDP-GlcNAc 2-epimerases/N-acetylmannosamine kinase; NCAM, neural cell adhesion molecule; polySia, polysialic acid; Sia, sialic acid; ST8Sia, polysialyltransferase.

Figure 3

Sia on gangliosides and its role in neurotransmission. Figure modified from Karim and Wang (1) with kind permission from CAB Reviews. Sia residues on gangliosides around the synaptic cleft are thought to modulate Ca2+ levels via Ca2+-ganglioside interactions (1). During the resting potential, the presynaptic membrane is closed due to tight Ca2+-ganglioside associations with the aid of negative charges from terminally positioned Sia. When an action potential reaches the presynaptic membrane, the electric field strength and/or changes in ion concentration occur. This results in the rearrangement of gangliosides and release of Ca2+ from its binding sites, altering membrane permeability and leading to the influx of Ca2+ through ion channels into the pre-synapse (2). Increased Ca2+ initiates a number of intracellular responses and signal cascades and causes transmitter release (3). Neurotransmitters bind to specific receptors on the postsynaptic membrane, allowing the influx of sodium ions and resulting in a local depolarization of the post-synapse (4). The resting potential is restored as the transmitter degrades and Ca2+ is returned to the extracellular space by ganglioside-modulated Ca2+-ATPase, allowing the tight membrane Ca2+-ganglioside interaction to reform. Sia, sialic acid.